Controlling the input that arrives at the primary visual cortex (V1) from the eyes is a powerful means for altering the outcome of all subsequent processing of visual information. That the strength (or gain) of this visual input to cortex can be dynamically modified is not controversial, but debate continues regarding the means by which that gain control is achieved. Currently, there are well-described mechanisms for modifying the strength of visual input based on other visual input (such as contrast gain control and normalization). However, modification of cortical processing by behavioral and cognitive states (such as attention) almost certainly arises from circuits outside the visual pathway, and we know far less about how this extra-retinal control of vision is achieved. Anatomical studies in macaque monkeys indicate that modulation by the cholinergic and serotonergic systems is strongly directed toward the site of visual input to cortex ? the thalamic-recipient layer (4c) in V1. This localization positions the cholinergic and serotonergic systems to control the extent to which information from the eyes gets processed, and therefore whether and how it is perceived. We hypothesize that acetylcholine and serotonin bi-directionally control the ?gate? to cortex, such that acetylcholine increases (and serotonin decreases) the strength of the input from the eyes. We will causally manipulate this modulatory control of layer 4c during active vision, and determine the resulting effects on both neural responses and behavior. At the neural level, we will determine the extent to which gain changes induced in layer 4c propagate to other layers, including the conditions under which propagation occurs, and the form the propagated signal takes. We will also determine the impact of these gain effects on behavior. Understanding how neuromodulators allow state variables (such as arousal and motivation) to dynamically rebalance cortical processing is critically important: Eight of the ten most-prescribed psychiatric drugs target neuromodulatory systems, as does the only approved drug treatment for dementia. Thus, it is through controlling neuromodulators that we (and the brain) modify perception, cognition, and behavior. It is generally assumed that these drugs act by altering late-stage cortical processing, but the anatomy points us towards a concurrent early modification of cortical input. We will elucidate the mechanism(s) behind, and determine the consequences of, that early control upon which all later processing depends.